Total Synthesis of the Euphorbia Diterpenoid Pepluacetal

The first total synthesis of the Euphorbia diterpenoid pepluacetal is disclosed in both racemic and chiral fashions. The synthesis strategically relies on a photo-induced Wolff rearrangement/lactonization cascade (WRLC) reaction to access the cyclobutane moiety, a ring-closing metathesis/cyclopropanation sequence to rapidly forge the 7-3 bicyclic system, and a late-stage Rh-catalyzed transannular carbenoid insertion to C(sp³)-H bond followed by a Baeyer-Villiger oxidation and ring-opening manipulations to install the side chain. The synthetic route demonstrates excellent stereochemical control on the non-classical concave-face bond formation, remote traceless stereochemical relay and high scalability to provide 20 mg of (+)-pepluacetal.